Genetics of Atrial Fibrillation

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia with poor prognosis, reaching epidemic proportions in the ageing population. The condition affects more than five million people worldwide and is a significant clinical problem. Of particular interest is a subset of younger patients (<60 years of age) who develop AF in the absence of known risk factors (such as advancing age, hypertension, structural heart disease and congestive heart failure), a condition classified as lone AF. Genetic variations in ion channel genes only account for a small percentage of the cases. Genome‐wide association studies (GWAS) look beyond the targeted genes and are capable of identifying novel mutations and genes, and biological pathways for AF. This review summarises the candidate gene and GWAS on AF, and discusses the application of exome sequencing approach in revisiting familial AF, as well as the potential clinical applications of the genetic data in the management of AF. A better understanding of the molecular mechanism of AF will aid the cardiologist in strategising the optimal therapeutic regimen for the patient.

Key Concepts:

  • Atrial fibrillation is an important clinical problem.

  • Atrial fibrillation is associated with genetic mutations in ion channel genes.

  • Genetic mutations often exhibit incomplete penetrance.

  • Genetic mutations may have functional impact on the ion channel.

  • Single‐nucleotide polymorphisms in ion channel genes only account for a small percentage of the cases.

  • The technology for identifying genetic variations is advancing rapidly.

  • Next‐generation sequencing is expected to become increasingly feasible.

  • The genetic data garnered from candidate gene and genome‐wide association studies have important clinical implications in management and treatment strategies of atrial fibrillation.

Keywords: atrial fibrillation; arrhythmias; genetic biomarkers; ion channels; genome‐wide association studies; candidate gene sequencing; exome sequencing

Figure 1.

Schematic diagram illustrating the diverse genetic causes of atrial fibrillation.

close

References

Andalib A, Brugada R and Nattel S (2008) Atrial fibrillation: evidence for genetically determined disease. Current Opinion in Cardiology 23: 176–183.

Antzelevitch C, Pollevick GD, Cordeiro JM et al. (2007) Loss‐of‐function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST‐segment elevation, short QT intervals, and sudden cardiac death. Circulation 115: 442–449.

Arnar DO, Thorvaldsson S, Manolio TA et al. (2006) Familial aggregation of atrial fibrillation in Iceland. European Heart Journal 27: 708–712.

Benjamin EJ, Levy D, Vaziri SM et al. (1994) Independent risk factors for atrial fibrillation in a population‐based cohort. The Framingham Heart Study. Journal of the American Medical Association 271: 840–844.

Benjamin EJ, Rice KM, Arking DE et al. (2009) Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nature Genetics 41: 879–881.

Brugada R, Brugada J, Antzelevitch C et al. (2000) Sodium channel blockers identify risk for sudden death in patients with ST‐segment elevation and right bundle branch block but structurally normal hearts. Circulation 101: 510–515.

Brugada R, Tapscott T, Czernuszewicz GZ et al. (1997) Identification of a genetic locus for familial atrial fibrillation. New England Journal of Medicine 336: 905–911.

Chambers JC, Zhao J, Terracciano CM et al. (2010) Genetic variation in SCN10A influences cardiac conduction. Nature Genetics 42: 149–152.

Chen LY, Ballew J, Herron K et al. (2007) A common polymorphism in SCN5A is associated with lone atrial fibrillation. Clinical Pharmacology and Therapeutics 81: 35–41.

Chen YH, Xu SJ, Bendahhou S et al. (2003) KCNQ1 gain‐of‐function mutation in familial atrial fibrillation. Science 299: 251–254.

Darbar D, Herron KJ, Ballew JD et al. (2003) Familial atrial fibrillation is a genetically heterogeneous disorder. Journal of the American College of Cardiology 41: 2185–2192.

Ellinor PT, Lunetta KL, Glazer NL et al. (2010) Common variants in KCNN3 are associated with lone atrial fibrillation. Nature Genetics 42: 240–244.

Ellinor PT, Moore RK, Patton KK et al. (2004) Mutations in the long QT gene, KCNQ1, are an uncommon cause of atrial fibrillation. Heart 90: 1487–1488.

Ellinor PT, Nam EG, Shea MA et al. (2008) Cardiac sodium channel mutation in atrial fibrillation. Heart Rhythm 5: 99–105.

Ellinor PT, Petrov‐Kondratov VI, Zakharova E et al. (2006) Potassium channel gene mutations rarely cause atrial fibrillation. Biomed Central Medical Genetics 7: 70.

Ellinor PT, Shin JT, Moore RK et al. (2003) Locus for atrial fibrillation maps to chromosome 6q14–16. Circulation 107: 2880–2883.

Ellinor PT, Yoerger DM, Ruskin JN et al. (2005) Familial aggregation in lone atrial fibrillation. Human Genetics 118: 179–184.

Fatini C, Sticchi E, Genuardi M et al. (2006) Analysis of minK and eNOS genes as candidate loci for predisposition to non‐valvular atrial fibrillation. European Heart Journal 27: 1712–1718.

Fox CS, Parise H, D'Agostino RB Sr et al. (2004) Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. Journal of the American Medical Association 291: 2851–2855.

Gollob MH, Jones DL, Krahn AD et al. (2006) Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. New England Journal of Medicine 354: 2677–2688.

Gretarsdottir S, Thorleifsson G, Manolescu A et al. (2008) Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Annals of Neurology 64: 402–409.

Gudbjartsson DF, Arnar DO, Helgadottir A et al. (2007) Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 448: 353–357.

Gudbjartsson DF, Holm H, Gretarsdottir S et al. (2009) A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nature Genetics 41: 876–878.

Hodgson‐Zingman DM, Karst ML, Zingman LV et al. (2008) Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. New England Journal of Medicine 359: 158–165.

Holm H, Gudbjartsson DF, Arnar DO et al. (2010) Several common variants modulate heart rate, PR interval and QRS duration. Nature Genetics 42: 117–122.

Hong K, Bjerregaard P, Gussak I et al. (2005) Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. Journal of Cardiovascular Electrophysiology 16: 394–396.

Husser D, Adams V, Piorkowski C et al. (2010) Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation. Journal of the American College of Cardiology 55: 747–753.

Kato K, Oguri M, Hibino T et al. (2007) Genetic factors for lone atrial fibrillation. International Journal of Molecular Medicine 19: 933–939.

Kopecky SL, Gersh BJ, McGoon MD et al. (1987) The natural history of lone atrial fibrillation. A population‐based study over three decades. New England Journal of Medicine 317: 669–674.

Krahn AD, Manfreda J, Tate RB et al. (1995) The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow‐Up Study. American Journal of Medicine 98: 476–484.

Ku CS and Chia KS (2008) The success of the genome‐wide association approach: a brief story of a long struggle. European Journal of Human Genetics 15: 554–564.

Ku CS, Loy EY, Pawitan Y et al. (2010) The pursuit of genome wide association studies: where are we now? Journal of Human Genetics 55: 195–206.

Ku CS, Naidoo N and Pawitan Y (2011) Revisiting Mendelian disorders through exome sequencing. Human Genetics 129: 351–370.

Kuhlenbäumer G, Hullmann J and Appenzeller S (2011) Novel genomic techniques open new avenues in the analysis of monogenic disorders. Human Mutation 32: 144–151.

Lai LP, Su MJ, Yeh HM et al. (2002) Association of the human minK gene 38G allele with atrial fibrillation: evidence of possible genetic control on the pathogenesis of atrial fibrillation. American Heart Journal 144: 485–490.

Larson MG, Atwood LD, Benjamin EJ et al. (2007) Framingham Heart Study 100K project: genome‐wide associations for cardiovascular disease outcomes. Biomed Central Medical Genetics 8(Suppl 1): S5.

Lemmens R, Buysschaert I, Geelen V et al. (2010) International Stroke Genetics Consortium The association of the 4q25 susceptibility variant for atrial fibrillation with stroke is limited to stroke of cardioembolic etiology. Stroke 41: 1850–1857.

Li C, Wang F, Yang Y et al. (2011) Significant association of SNP rs2106261 in the ZFHX3 gene with atrial fibrillation in a Chinese Han GeneID population. Human Genetics 129: 239–246.

Lip GY (2007) Coronary artery disease and ischemic stroke in atrial fibrillation. Chest 132: 8–10.

Liu X, Wang F, Knight AC et al. (2011) Common variants for atrial fibrillation: results from genome‐wide association studies. Human Genetics [Epub ahead of print].

Mahida S, Lubitz SA, Rienstra M et al. (2011) Monogenic atrial fibrillation as pathophysiological paradigms. Cardiovascular Research 89: 692–700.

McNair WP, Ku L, Taylor MR et al. (2004) Familial Cardiomyopathy Registry Research Group. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 110: 2163–2167.

Morrison AC, Bare LA, Chambless LE et al. (2007) Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. American Journal of Epidemiology 166: 28–35.

Newton‐Cheh C, Eijgelsheim M, Rice KM et al. (2009) Common variants at ten loci influence QT interval duration in the QTGEN Study. Nature Genetics 41: 399–406.

Newton‐Cheh C, Guo CY, Wang TJ et al. (2007) Genome‐wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study. BioMed Central Medical Genetics 8(suppl. 1): S7.

Ng SB, Bigham AW and Buckingham KJ (2010a) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature Genetics 42: 790–793.

Ng SB, Nickerson DA, Bamshad MJ et al. (2010b) Massively parallel sequencing and rare disease. Human Molecular Genetics 19: R119–R124.

Ng SB, Turner EH, Robertson PD et al. (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461: 272–276.

Olson TM, Alekseev AE, Liu XK et al. (2006) Kv1.5 channelopathy due to KCNA5 loss‐of‐function mutation causes human atrial fibrillation. Human Molecular Genetics 15: 2185–2191.

Olson TM, Michels VV, Ballew JD et al. (2005) Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. Journal of American Medical Association 293: 447–454.

Olsson SB, Cotoi S and Varnauskas E (1971) Monophasic action potential and sinus rhythm stability after conversion of atrial fibrillation. Acta Medica Scandinavia 190: 381–387.

Pencina MJ, D'Agostino RB Sr, D'Agostino RB Jr et al. (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Statistics in Medicine 27: 157–172.

Pfeufer A, Sanna S, Arking DE et al. (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nature Genetics 41: 407–414.

Pfeufer A, van Noord C, Marciante KD et al. (2010) Genome‐wide association study of PR interval. Nature Genetics 42: 153–159.

Psaty BM, Manolio TA, Kuller LH et al. (1997) Incidence of and risk factors for atrial fibrillation in older adults. Circulation 96: 2455–2461.

Ravn LS, Hofman‐Bang J, Dixen U et al. (2005) Relation of 97 T polymorphism in KCNE5 to risk of atrial fibrillation. American Journal of Cardiology 96: 405–407.

Roberts JD and Gollob MH (2010) Impact of genetic discoveries on the classification of lone atrial fibrillation. Journal of the American College of Cardiology 55: 705–712.

Roden DM (1998) Mechanisms and management of proarrhythmia. American Journal of Cardiology 82: 49I–57I.

Saksena S and Camm JA (2004) Electrophysiological Disorders of the Heart. Philadephia: Elsevier Churchill Livingstone.

Sandhu MS, Weedon MN, Fawcett KA et al. (2007) Common variants in WFS1 confer risk of type 2 diabetes. Nature Genetics 39: 951–953.

Schreieck J, Dostal S, von Beckerath N et al. (2004) C825T polymorphism of the G‐protein beta3 subunit gene and atrial fibrillation: association of the TT genotype with a reduced risk for atrial fibrillation. American Heart Journal 148: 545–550.

Shi L, Li C, Wang C et al. (2009) Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population. Human Genetics 126: 843–849.

Smith JG, Lowe JK, Kovvali S et al. (2009) Genome‐wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae. Heart Rhythm 6: 634–641.

Smith JG, Magnani JW, Palmer C et al. (2011) Genome‐wide association studies of the PR interval in African Americans. Public Library of Science Genetics 7: e1001304.

Sorbera LA and Morad M (1990) Atrionatriuretic peptide transforms cardiac sodium channels into calcium‐conducting channels. Science 247: 969–973.

Sotoodehnia N, Isaacs A, de Bakker PI et al. (2010) Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nature Genetics 42: 1068–1076.

Stewart S, Hart CL, Hole DJ et al. (2002) A population‐based study of the long‐term risks associated with atrial fibrillation: 20‐year follow‐up of the Renfrew/Paisley study. American Journal of Medicine 113: 359–364.

Tsai CT, Lai LP, Lin JL et al. (2004) Renin‐angiotensin system gene polymorphisms and atrial fibrillation. Circulation 109: 1640–1646.

Winckler W, Weedon MN, Graham RR et al. (2007) Evaluation of common variants in the six known maturity‐onset diabetes of the young (MODY) genes for association with type 2 diabetes. Diabetes 56: 685–693.

Xia M, Jin Q, Bendahhou S et al. (2005) A Kir2.1 gain‐of‐function mutation underlies familial atrial fibrillation. Biochemical and Biophysical Research Communication 332: 1012–1019.

Xiao J, Liang D and Chen YH (2011) The genetics of atrial fibrillation: From the bench to the bedside. Annual Review of Genomics and Human Genetics 12: 73–96.

Yang Y, Li J, Lin X et al. (2009) Novel KCNA5 loss‐of‐function mutations responsible for atrial fibrillation. Journal of Human Genetics 54: 277–283.

Yang Y, Xia M, Jin Q et al. (2004) Identification of a KCNE2 gain‐of‐function mutation in patients with familial atrial fibrillation. American Journal of Human Genetics 75: 899–905.

Zeng Z, Tan C, Teng S et al. (2007) The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population. Cardiology 108: 97–103.

Further Reading

Chugh SS, Blackshear JL, Shen WK et al. (2001) Epidemiology and natural history of atrial fibrillation: clinical implications. Journal of the American College of Cardiology 37: 371–378.

Damani SB and Topol EJ (2009) Molecular genetics of atrial fibrillation. Genome Medicine 1: 54.

Ellinor PT, Yi BA and MacRae CA (2008) Genetics of atrial fibrillation. Medical Clinics of North America 92: 41–51.

Hirschhorn JN (2005) Genetic and genomic approaches to studying stature and pubertal timing. Pediatric Endocrinology Reviews 2: 351–354.

Koo SH, Ho WF and Lee EJ (2006) Genetic polymorphisms in KCNQ1, HERG, KCNE1 and KCNE2 genes in the Chinese, Malay and Indian populations of Singapore. British Journal of Clinical Pharmacology 61: 301–308.

Ku CS, Loy EY, Salim A et al. (2010) The discovery of human genetic variations and their use as disease markers: past, present and future. Journal of Human Genetics 55: 403–415.

Lubitz SA, Ozcan C, Magnani JW et al. (2010) Genetics of atrial fibrillation: implications for future research directions and personalized medicine. Circulation: Arrhythmia and Electrophysiology 3: 291–299.

Milan DJ, Lubitz SA, Kääb S et al. (2010) Genome‐wide association studies in cardiac electrophysiology: recent discoveries and implications for clinical practice. Heart Rhythm 7: 1141–1148.

Polychronakos C and Seng KC (2011) Exome diagnostics: already a reality? Journal of Medical Genetics 48: 579.

Sinner MF, Ellinor PT, Meitinger T et al. (2011) Genome‐wide association studies of atrial fibrillation: past, present, and future. Cardiovascular Research 89: 701–709.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Koo, Seok Hwee, Ku, Chee Seng, Chen, Lin Yee, and Lee, Edmund Jon Deoon(Nov 2011) Genetics of Atrial Fibrillation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023215]